The molecular/biochemical bases of parasite responses to the potentially hostile environment of the host form the central theme around which this overall program is based. This program proposal does not address host responses to parasites, but rather addresses the basis for successful parasitism at the molecular level. Parasites are very adept at switching genes on and off in response to environmental clues and as a result have evolved numerous mechanisms to ensure their survival in both their definitive and intermediate hosts. It is the interplay of parasite and host genes that determines the success or failure of host exploitation by parasites; therefore, we can learn a great deal by investigating the molecular determinants of successful parasite-host interactions. All of the research projects outlined in this proposal address this theme with different host-parasite systems of major consequence to human health in the tropics. Project I is an investigation of virulence-associated gene expression independent of antigenic variation associated with variant surface glycoproteins in Trypanosoma brucei rhodesiense. Project2 uses the Plasmodium yoelli -mouse model to assess the dynamic interplay of host and parasite genes as this relates to the success of the parasite-host association. Project 3 addresses the fundamental question of how parasites genetically adapt to abrupt changes in their host environment by investigating proximal enzyme activation of drugs within Schistosoma mansoni. Adaptive parasite responses to the host environment also is the emphasis of Project 4. This project will investigate the molecular mechanisms underlying S. mansoni-mediated castration of the snail vector, Biomphalaria glabrata. Project 5 is designed to isolate the genes responsible for susceptibility of Aedes aegypti to filarial worms (Brugia malayi and Dirofilaria immitis), and to characterize their products to determine how they influence gene expression within the parasite. Each of these projects by themselves would provide a significant contribution to our understanding of tropical parasitology, but the interaction and collaborative nature of this program project will provide an even greater insight into the molecular basis of parasite-host associations. Present and future methods aimed at controlling or eliminating parasitic diseases would obviously benefit from an increased understanding of how parasite and host genes influence the adaptability of the parasite to the host environment.